Obesity is a serious and growing public health problem in the United States and the world. The processes that underlie this increasing prevalence of obesity have not been clearly defined but likely involve faulty interactions between environmental factors with weight regulatory systems in genetically susceptible individuals. Those who are genetically predisposed to thinness in the current environment may be able to sense and respond to excess energy intake more rapidly and accurately than those predisposed to obesity. We have observed that thin (obese-resistant) individuals quickly sense changes in energy balance with significant changes in subjective measures of hunger and satiety. This is in contrast to reduced-obese (obese prone) individuals who do not appear to appropriately sense short-term changes in energy intake. It therefore appears that there is a central regulation of ingestive behaviors which is altered by changes in energy balance, and that this regulation is more or less sensitive dependent on the phenotype. What is it about our response to energy balance that leads to changes in behaviors? The role of the brain in the regulation of energy balance has long been recognized and has been an area of intensive research. A great deal has been learned about the hypothalamic regulation of food intake and interactions with adiposity signals such as leptin. It is clear, however, that the intake of food is a much more complex process, especially in humans in which psychosocial factors play a critical role and in which the process of eating is likely to be controlled by reward and learned behaviors. Our long term goal is to gain a better understanding of the central regulation of ingestive behavior. In addition, we are interested in understanding the adaptations to changes in energy balance (short-term over and under feeding) in thin individuals who appear to be genetically resistant to weight gain and obesity as compared to individuals at risk for weight gain and obesity. The central hypothesis of the proposed research is that the regulation of food intake is a complex process requiring the integration of multiple sensory inputs and learned behaviors in the context of background energy balance. Specifically, the motivational state of the individual as manipulated by changes in energy balance will result in the activation or inhibition of specific brain regions involved with the processing and integration of the incentive value and reward of food, and these changes neuronal activity will be associated with feeding behaviors. Understanding the behavioral and central neuronal responses of thin individuals to short periods of varying energy balance will provide clues to the mechanisms that may protect against weight gain in the current environment. The proposed studies will examine the effects of eucaloric intake, overfeeding, or underfeeding on: 1) regional cerebral neuronal activity, 2) hunger, satiety, hedonics, cue- elicited food craving, and spontaneous food intake, and 3) the correlation between changes in neuronal activity and behavioral measures in men and women screened to be either resistant or prone to weight gain and obesity. [unreadable] [unreadable] [unreadable]